Transgenic Drosophila melanogaster Carrying a Human Full-Length DISC1 Construct (UAS-hflDISC1) Showing Effects on Social Interaction Networks.

Disrupted in Schizophrenia 1 (DISC1) is a scaffold protein implicated in major mental illnesses including schizophrenia, with a significant negative impact on social life. To investigate if DISC1 affects social interactions in Drosophila melanogaster, we created transgenic flies with second or third chromosome insertions of the human full-length DISC1 (hflDISC1) gene fused to a UAS promotor (UAS-hflDISC1). Initial characterization of the insertion lines showed unexpected endogenous expression of the DISC1 protein that led to various behavioral and neurochemical phenotypes. Social interaction network (SIN) analysis showed altered social dynamics and organizational structures. This was in agreement with the altered levels of the locomotor activity of individual flies monitored for 24 h. Together with a decreased ability to climb vertical surfaces, the observed phenotypes indicate altered motor functions that could be due to a change in the function of the motor neurons and/or central brain. The changes in social behavior and motor function suggest that the inserted hflDISC1 gene influences nervous system functioning that parallels symptoms of DISC1-related mental diseases in humans. Furthermore, neurochemical analyses of transgenic lines revealed increased levels of hydrogen peroxide and decreased levels of glutathione, indicating an impact of DISC1 on the dynamics of redox regulation, similar to that reported in transgenic mammals. Future studies are needed to address the localization of DISC1 expression and to address how the redox parameter changes correlate with the observed behavioral changes.

Disrupted-in-schizophrenia 1 protein aggregates in cerebrospinal fluid are elevated in patients with first-episode psychosis.

AIM: The disrupted-in-schizophrenia 1 (DISC1) protein is a key regulator at the intersection of major signaling pathways relevant for adaptive behavior. It is prone to posttranslational changes such as misassembly and aggregation but the significance of such transformations for human mental illness has remained unclear. We aimed to demonstrate the occurrence of DISC1 protein aggregates in patients with first-episode psychosis (FEP). METHOD: Cerebrospinal fluid samples of patients with FEP (n = 50) and matched healthy controls (HCs; n = 47) were measured by the highly sensitive surface-based fluorescence intensity distribution analysis technology that enables single aggregate detection. RESULTS: We demonstrate that DISC1 protein aggregates are increased in cerebrospinal fluid samples of patients with FEP versus HCs. The concentration was in the low femtomolar range. No correlations were found with specific symptom levels, but the difference was particularly significant in the subset of patients with the diagnoses schizophrenia, unspecified (DSM-IV 295.9) or schizoaffective disorder (DSM-IV 295.70) at 18-month follow-up. DISC1 protein aggregate levels did not significantly change within the 18-month observation interval and were on average higher for individuals carrying the major DISC1 rs821577 allele, before correction. CONCLUSION: The occurrence of protein aggregates in vivo in patients with psychotic disorders has not been previously reported. It underscores the significance of posttranslational modifications of proteins both as pathogenetic mechanisms and as potential diagnostic markers in these disorders.

Advantages and Limitations of Animal Schizophrenia Models.

Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.

DISC1 gene polymorphisms and the risk of schizophrenia in an Iranian population: A preliminary study.

BACKGROUND: Schizophrenia, schizoaffective disorder, and bipolar illness are common psychological disorders with high heritability and variable phenotypes. The disrupted in schizophrenia 1 ( DISC1) gene, on chromosome 1q42, has an essential role in neurite outgrowth and cell signaling. The purpose of this study was to investigate the association of three single-nucleotide polymorphisms (SNPs; rs6675281, rs2255340, and rs2738864) with schizophrenia disorder. These three SNPs were chosen as they had been used in most of the previous studies. METHODS: In a case-control study of Iranian population for the first time 778 blood samples were collected including, 402 schizophrenic patients and 376 healthy controls. Genomic DNA was extracted from peripheral blood using DNA extraction kit (BioFlux Co). The genotypes of rs6675281, rs2255340, and rs2738864 were detected by nested allele-specific multiplex polymersae chain reaction (PCR). RESULTS: Our data revealed that the three SNPs are significantly associated with schizophrenia (rs2255349 C>T: confidence interval (CI), 2.115 to 3.268; P = 0.0000 OR: 2.629; rs2738864 C>T: CI, 1.538 to 2.339; P = 0.0000 OR: 1.897; rs6675281 C>T: CI, 2.788 to 4.662; P = 0.0009241 OR: 3.605). Through applying the expectation-maximization (EM) algorithm, we calculated the haplotype frequency, and finally performed haplotype analysis with Bonferroni correction and data preprocessing methods and the results showed rs66875281 to have the highest association. DISCUSSION: Our findings primarily showed that DISC1 gene polymorphisms contribute to schizophrenia risk and have a significant association with this disorder among Iranian population. The strategy was found to be easy, rapid, specific, and consistent for the co-occurring detection of the DISC1 polymorphisms. We could finally confirm that the polymorphisms are related to schizophrenia studied in Iranian population.

Caveolin-1 regulation of disrupted-in-schizophrenia-1 as a potential therapeutic target for schizophrenia.

Schizophrenia is a debilitating psychiatric disorder manifested in early adulthood. Disrupted-in-schizophrenia-1 (DISC1) is a susceptible gene for schizophrenia (Hodgkinson et al. 2004; Millar et al. 2000; St Clair et al. 1990) implicated in neuronal development, brain maturation, and neuroplasticity (Brandon and Sawa 2011; Chubb et al. 2008). Therefore, DISC1 is a promising candidate gene for schizophrenia, but the molecular mechanisms underlying its role in the pathogenesis of the disease are still poorly understood. Interestingly, caveolin-1 (Cav-1), a cholesterol binding and scaffolding protein, regulates neuronal signal transduction and promotes neuroplasticity. In this study we examined the role of Cav-1 in mediating DISC1 expression in neurons in vitro and the hippocampus in vivo. Overexpressing Cav-1 specifically in neurons using a neuron-specific synapsin promoter (SynCav1) increased expression of DISC1 and proteins involved in synaptic plasticity (PSD95, synaptobrevin, synaptophysin, neurexin, and syntaxin 1). Similarly, SynCav1-transfected differentiated human neurons derived from induced pluripotent stem cells (hiPSCs) exhibited increased expression of DISC1 and markers of synaptic plasticity. Conversely, hippocampi from Cav-1 knockout (KO) exhibited decreased expression of DISC1 and proteins involved in synaptic plasticity. Finally, SynCav1 delivery to the hippocampus of Cav-1 KO mice and Cav-1 KO neurons in culture restored expression of DISC1 and markers of synaptic plasticity. Furthermore, we found that Cav-1 coimmunoprecipitated with DISC1 in brain tissue. These findings suggest an important role by which neuron-targeted Cav-1 regulates DISC1 neurobiology with implications for synaptic plasticity. Therefore, SynCav1 might be a potential therapeutic target for restoring neuronal function in schizophrenia. NEW & NOTEWORTHY: The present study is the first to demonstrate that caveolin-1 can regulate DISC1 expression in neuronal models. Furthermore, the findings are consistent across three separate neuronal models that include rodent neurons (in vitro and in vivo) and human differentiated neurons derived from induced pluripotent stem cells. These findings justify further investigation regarding the modulatory role by caveolin on synaptic function and as a potential therapeutic target for the treatment of schizophrenia.

Deficits in axon-associated proteins in prefrontal white matter in bipolar disorder but not schizophrenia.

OBJECTIVES: Brain imaging studies have implicated white matter dysfunction in the pathophysiology of both bipolar disorder (BD) and schizophrenia (SCZ). However, the contribution of axons to white matter pathology in these disorders is not yet understood. Maintenance of neuronal function is dependent on the active transport of biological material, including synaptic proteins, along the axon. In this study, the expression of six proteins associated with axonal transport of synaptic cargoes was quantified in postmortem samples of prefrontal white matter in subjects with BD, those with SCZ, and matched controls, as a measure of axonal dysfunction in these disorders. METHODS: Levels of the microtubule-associated proteins ß-tubulin and microtubule-associated protein 6 (MAP6), the motor and accessory proteins kinesin-1 and disrupted-in-schizophrenia 1 (DISC1), and the synaptic cargoes synaptotagmin and synaptosomal-associated protein-25 (SNAP-25) were quantified in white matter adjacent to the dorsolateral prefrontal cortex in subjects with BD (n = 34), subjects with SCZ (n = 35), and non-psychiatric controls (n = 35) using immunoblotting and an enzyme-linked immunosorbent assay (ELISA). RESULTS: Protein expression of ß-tubulin, kinesin-1, DISC1, synaptotagmin, and SNAP-25 was significantly lower in subjects with BD compared to controls. Levels of axon-associated proteins were also lower in subjects with SCZ, but failed to reach statistical significance. CONCLUSIONS: These data provide evidence for deficits in axon-associated proteins in prefrontal white matter in BD. Findings are suggestive of decreased axonal density or dysregulation of axonal function in this disorder.

Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid schizophrenia.

Profound white matter abnormalities have repeatedly been described in schizophrenia, which involve the altered expression of numerous oligodendrocyte-associated genes. Transcripts of the disrupted-in-schizophrenia 1 (DISC1) gene, a key susceptibility factor in schizophrenia, have recently been shown to be expressed by oligodendroglial cells and to negatively regulate oligodendrocyte differentiation and maturation. To learn more about the putative role(s) of oligodendroglia-associated DISC1 in schizophrenia, we analyzed the density of DISC1-immunoreactive oligodendrocytes in the fronto-parietal white matter in postmortem brains of patients with schizophrenia. Compared with controls (N = 12) and cases with undifferentiated/residual schizophrenia (N = 6), there was a significantly increased density of DISC1-expressing glial cells in paranoid schizophrenia (N = 12), which unlikely resulted from neuroleptic treatment. Pathophysiologically, over-expression of DISC1 protein(s) in white matter oligodendrocytes might add to the reduced levels of two myelin markers, 2',3'-cyclic-nucleotide 3'-phosphodiesterase and myelin basic protein in schizophrenia. Moreover, it might significantly contribute to cell cycle abnormalities as well as to deficits in oligodendroglial cell differentiation and maturation found in schizophrenia.

Common variants in psychiatric risk genes predict brain structure at birth.

Studies in adolescents and adults have demonstrated that polymorphisms in putative psychiatric risk genes are associated with differences in brain structure, but cannot address when in development these relationships arise. To determine if common genetic variants in disrupted-in-schizophrenia-1 (DISC1; rs821616 and rs6675281), catechol-O-methyltransferase (COMT; rs4680), neuregulin 1 (NRG1; rs35753505 and rs6994992), apolipoprotein E (APOE; ε3ε4 vs. ε3ε3), estrogen receptor alpha (ESR1; rs9340799 and rs2234693), brain-derived neurotrophic factor (BDNF; rs6265), and glutamate decarboxylase 1 (GAD1; rs2270335) are associated with individual differences in brain tissue volumes in neonates, we applied both automated region-of-interest volumetry and tensor-based morphometry to a sample of 272 neonates who had received high-resolution magnetic resonance imaging scans. ESR1 (rs9340799) predicted intracranial volume. Local variation in gray matter (GM) volume was significantly associated with polymorphisms in DISC1 (rs821616), COMT, NRG1, APOE, ESR1 (rs9340799), and BDNF. No associations were identified for DISC1 (rs6675281), ESR1 (rs2234693), or GAD1. Of note, neonates homozygous for the DISC1 (rs821616) serine allele exhibited numerous large clusters of reduced GM in the frontal lobes, and neonates homozygous for the COMT valine allele exhibited reduced GM in the temporal cortex and hippocampus, mirroring findings in adults. The results highlight the importance of prenatal brain development in mediating psychiatric risk.

Impact of COMT, PRODH and DISC1 Genetic Variants on Cognitive Performance of Patients with Schizophrenia.

BACKGROUND: Cognitive impairment in schizophrenia (SCZ) is a core feature, relevant for the disease prognosis and functional capacity of the patients. It has also been identified as an endophenotype and proposed as a genetic mechanism of risk for schizophrenia. AIM OF THE STUDY: We aimed to evaluate the association of genetic variants in COMT, PRODH, and DISC1 with the cognitive performance of Mexican-Mestizo adult patients with SCZ in order to identify endophenotypes. SUBJECTS AND METHODS: The association of seven variants in COMT, 15 in PRODH, and three in DISC1 was evaluated in 150 patients and 150 control volunteers. The MATRICS Consensus Cognitive Battery was administered to a subset of 44 patients and 42 controls. RESULTS: COMT rs4633 was related to MATRICS global assessment, while in the multi-phenotype analysis, PRODH rs2870984 was associated with processing speed, working memory, verbal learning, and social cognition. In addition, the association of variants in COMT and PRODH with the risk for SCZ was also found in Mexican-Mestizo patients. CONCLUSION: COMT might be a potential biomarker of cognitive impairment in Mexican-Mestizo patients with SCZ, supporting the relevance of this gene for drug design.

Restoration of mitochondria axonal transport by adaptor Disc1 supplementation prevents neurodegeneration and rescues visual function.

Deficits in mitochondrial transport are a common feature of neurodegenerative diseases. We investigated whether loss of components of the mitochondrial transport machinery impinge directly on metabolic stress, neuronal death, and circuit dysfunction. Using multiphoton microscope live imaging, we showed that ocular hypertension, a major risk factor in glaucoma, disrupts mitochondria anterograde axonal transport leading to energy decline in vulnerable neurons. Gene- and protein-expression analysis revealed loss of the adaptor disrupted in schizophrenia 1 (Disc1) in retinal neurons subjected to high intraocular pressure. Disc1 gene delivery was sufficient to rescue anterograde transport and replenish axonal mitochondria. A genetically encoded ATP sensor combined with longitudinal live imaging showed that Disc1 supplementation increased ATP production in stressed neurons. Disc1 gene therapy promotes neuronal survival, reverses abnormal single-cell calcium dynamics, and restores visual responses. Our study demonstrates that enhancing anterograde mitochondrial transport is an effective strategy to alleviate metabolic stress and neurodegeneration.

Parvalbumin Interneuron Dysfunction in a Thalamo-Prefrontal Cortical Circuit in Disc1 Locus Impairment Mice.

Altered cortical excitation-inhibition (E-I) balance resulting from abnormal parvalbumin interneuron (PV IN) function is a proposed pathophysiological mechanism of schizophrenia and other major psychiatric disorders. Preclinical studies have indicated that disrupted-in-schizophrenia-1 (Disc1) is a useful molecular lead to address the biology of prefrontal cortex (PFC)-dependent cognition and PV IN function. To date, PFC inhibitory circuit function has not been investigated in depth in Disc1 locus impairment (LI) mouse models. Therefore, we used a Disc1 LI mouse model to investigate E-I balance in medial PFC (mPFC) circuits. We found that inhibition onto layer 2/3 excitatory pyramidal neurons in the mPFC was significantly reduced in Disc1 LI mice. This reduced inhibition was accompanied by decreased GABA release from local PV, but not somatostatin (SOM) INs, and by impaired feedforward inhibition (FFI) in the mediodorsal thalamus (MD) to mPFC circuit. Our mechanistic findings of abnormal PV IN function in a Disc1 LI model provide insight into biology that may be relevant to neuropsychiatric disorders including schizophrenia.

Decreased nuclear distribution nudE-like 1 enzyme activity in an animal model with dysfunctional disrupted-in-schizophrenia 1 signaling featuring aberrant neurodevelopment and amphetamine-supersensitivity.

BACKGROUND: Interaction of nuclear-distribution element-like 1 with disrupted-in-schizophrenia 1 protein is crucial for neurite outgrowth/neuronal migration, and this interaction competitively inhibits nuclear-distribution element-like 1 peptidase activity. Nuclear-distribution element-like 1 activity is reduced in antipsychotic-naïve first-episode psychosis and in medicated chronic schizophrenia, with even lower activity in treatment-resistant schizophrenia. AIMS: The purpose of this study was to investigate in a rat model overexpressing human non-mutant disrupted-in-schizophrenia 1, with consequent dysfunctional disrupted-in-schizophrenia 1 signaling, the relation of nuclear-distribution element-like 1 activity with neurodevelopment and dopamine-related phenotypes. METHODS: We measured cell distribution in striatum and cortex by histology and microtomography, and quantified the basal and amphetamine-stimulated locomotion and nuclear-distribution element-like 1 activity (in blood and brain) of transgenic disrupted-in-schizophrenia 1 rat vs wild-type littermate controls. RESULTS: 3D assessment of neuronal cell body number and spatial organization of mercury-impregnated neurons showed defective neuronal positioning, characteristic of impaired cell migration, in striatum/nucleus accumbens, and prefrontal cortex of transgenic disrupted-in-schizophrenia 1 compared to wild-type brains. Basal nuclear-distribution element-like 1 activity was lower in the blood and also in several brain regions of transgenic disrupted-in-schizophrenia 1 compared to wild-type. Locomotion and nuclear-distribution element-like 1 activity were both significantly increased by amphetamine in transgenic disrupted-in-schizophrenia 1, but not in wild-type. CONCLUSIONS: Our findings in the transgenic disrupted-in-schizophrenia 1 rat allow us to state that decreased nuclear-distribution element-like 1 activity reflects both a trait (neurodevelopmental phenotype) and a state (amphetamine-induced dopamine release). We thus define here a role for decreased nuclear-distribution element-like 1 peptidase activity both for the developing brain (the neurodevelopmental phenotype) and for the adult (interaction with dopaminergic responses), and present nuclear-distribution element-like 1 activity in a novel way, as unifying neurodevelopmental with dysfunctional dopamine response phenotypes.

Expression of Behavioral Phenotypes in Genetic and Environmental Mouse Models of Schizophrenia.

Schizophrenia is a neuropsychiatric disorder characterized by multifactorial etiology involving complex interactions among genetic and environmental factors. "Multiple-hit" models of the disorder can explain its variable incidence and prevalence in related individuals. Hence, there is a dire need to understand these interactions in the emergence of schizophrenia. To test these factors in the emergence of schizophrenia-like behaviors, we employed a genetic mouse model of the disorder (harboring the DISC1 mutation) along with various environmental insults, such as early life stress (maternal separation of pups) and/or pharmacological interventions (ketamine injections). When assessed on a battery of behavioral tests, we found that environmental interventions affect the severity of behavioral phenotypes in terms of increased negative behavior, as shown by reduced mobility in the forced swim and tail suspension tests, and changes to positive and cognitive symptoms, such as increased locomotion and disrupted PPI along with reduced working memory, respectively. Among the various interventions, the genetic mutation had the most profound effect on behavioral aberrations, followed by an environmental intervention by ketamine injections and ketamine-injected animals that were maternally separated during early postnatal days. We conclude that although environmental factors increased the prevalence of aberrant behavioral phenotypes, genetic background is still the predominant influence on phenotypic alterations in these mouse models of schizophrenia.

Identification and Mechanistic Characterization of a Peptide Inhibitor of Glycogen Synthase Kinase (GSK3ß) Derived from the Disrupted in Schizophrenia 1 (DISC1) Protein.

Glycogen synthase kinase 3-beta (GSK3ß) is a critical regulator of several cellular pathways involved in neurodevelopment and neuroplasticity and as such is a potential focus for the discovery of new neurotherapeutics toward the treatment of neuropsychiatric and neurodegenerative diseases. The majority of efforts to develop inhibitors of GSK3ß have been focused on developing small molecule inhibitors that compete with adenosine triphosphate (ATP) through direct interaction with the ATP binding site. This strategy has presented selectivity challenges due to the evolutionary conservation of this domain within the kinome. The disrupted in schizophrenia 1 (DISC1) protein has previously been shown to bind and inhibit GSK3ß activity. Here, we report the characterization of a 44-mer peptide derived from human DISC1 (hDISCtide) that is sufficient to both bind and inhibit GSK3ß in a noncompetitive mode distinct from classical ATP competitive inhibitors. Based on multiple independent biochemical and biophysical assays, we propose that hDISCtide interacts at two distinct regions of GSK3ß: an inhibitory region that partially overlaps with the binding site of FRATide, a well-known GSK3ß binding peptide, and a specific binding region that is unique to hDISCtide. Taken together, our findings present a novel avenue for developing a peptide-based selective inhibitor of GSK3ß.

The DISC1 R264Q variant increases affinity for the dopamine D2 receptor and increases GSK3 activity.

The Disrupted in schizophrenia 1 (DISC1) gene encodes a scaffolding protein that is involved in many neural functions such as neurogenesis, neural differentiation, embryonic neuron migration and neurotransmitter signalling. DISC1 was originally implicated in schizophrenia in a single family with a drastic mutation, a chromosomal translocation severing the mid-point of the gene (aa 598). Some common DISC1 variants have also been associated with schizophrenia in the general population, but those located far from the chromosomal translocation breakpoint likely have a different functional impact. We previously reported that DISC1 forms a protein complex with dopamine D2 receptor (D2R), the main target for antipsychotic medications. The D2R-DISC1 complex is elevated in brain tissue from schizophrenia patients and facilitates glycogen synthase kinase (GSK)-3 signaling. The DISC1 R264Q variant is located within the region that binds the D2R, and we found that this polymorphism increases the affinity of DISC1 for the D2R and promotes GSK3 activity. Our results suggest a possible mechanism by which this common polymorphism could affect aspects of brain function that are relevant to psychosis and schizophrenia. This provides additional insight into molecular mechanisms underlying schizophrenia that could be exploited in the development of novel pharmacological treatments.

Disrupted-in-schizophrenia-1 protects synaptic plasticity in a transgenic mouse model of Alzheimer's disease as a mitophagy receptor.

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Accumulated damaged mitochondria, which are associated with impaired mitophagy, contribute to neurodegeneration in AD. We show levels of Disrupted-in-schizophrenia-1 (DISC1), which is genetically associated with psychiatric disorders and AD, decrease in the brains of AD patients and transgenic model mice and in Aß-treated cultured cells. Disrupted-in-schizophrenia-1 contains a canonical LC3-interacting region (LIR) motif (210 FSFI213 ), through which DISC1 directly binds to LC3-I/II. Overexpression of DISC1 enhances mitophagy through its binding to LC3, whereas knocking-down of DISC1 blocks Aß-induced mitophagy. We further observe overexpression of DISC1, but not its mutant (muFSFI) which abolishes the interaction of DISC1 with LC3, rescues Aß-induced mitochondrial dysfunction, loss of spines, suppressed long-term potentiation (LTP). Overexpression of DISC1 via adeno-associated virus (serotype 8, AAV8) in the hippocampus of 8-month-old APP/PS1 transgenic mice for 4 months rescues cognitive deficits, synaptic loss, and Aß plaque accumulation, in a way dependent on the interaction of DISC1 with LC3. These results indicate that DISC1 is a novel mitophagy receptor, which protects synaptic plasticity from Aß accumulation-induced toxicity through promoting mitophagy.

Neuronal serine racemase associates with Disrupted-In-Schizophrenia-1 and DISC1 agglomerates: Implications for schizophrenia.

D-Serine, an endogenous coagonist of N-methyl-d-aspartate receptors (NMDARs) at the glycine binding site, is synthesized by serine racemase (SR) through conversion of l-Serine. Dysregulation of SR/D-Serine and Disrupted-In-Schizophrenia-1 (DISC1) contributes to the pathogenesis of schizophrenia at converging pathways, as perturbation of SR-DISC1 binding in astrocytes elicits schizophrenia-like behaviors in mice. However, an association of neuronal SR with DISC1 remains elusive. Here we report that SR associates with DISC1 and its agglomerates in cortical neurons, which can be modulated by NMDAR activity. Endogenous SR colocalizes with DISC1 large agglomerates in the soma and with smaller puncta in the nucleus and dendrites of cortical neurons. Co-immunoprecipitation assays demonstrate SR interaction with DISC1 in cortical neuronal lysates, suggesting the physiological presence of functional SR-DISC1 complexes in neurons. Moreover, exogenous d-Serine application significantly increases the interaction of SR with DISC1, the number of DISC1-SR large agglomerates and the levels of DISC1 agglomerated form along with SR in the triton-insoluble pellet fraction, whereas application of glycine with a glycine transporter inhibitor fails to increase their interactions, abundance of DISC1-SR large agglomerates and levels of DISC1 agglomerated form. This increase by d-Serine application is blocked by 7-chlorokynurenic acid, a specific antagonist at the glycine site of NMDARs, suggesting mediation through NMDARs. Our findings thus demonstrate neuronal SR association with DISC1 and its agglomerates, which can be modulated by d-Serine, thereby validating a novel neuronal SR-DISC1 complex responsive to NMDAR activation and providing a molecular mechanism by which pathways implicated in schizophrenia converge.

Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats.

Synaptic pruning is a critical refinement step during neurodevelopment, and schizophrenia has been associated with overpruning of cortical dendritic spines. Both human studies and animal models implicate disrupted-in-schizophrenia 1 (DISC1) gene as a strong susceptibility factor for schizophrenia. Accumulating evidence supports the involvement of DISC1 protein in the modulation of synaptic elimination during critical periods of neurodevelopment and of dopamine D2-receptor-mediated signaling during adulthood. In many species, synaptic pruning occurs during juvenile and adolescent periods and is mediated by microglia, which can be over-activated by an immune challenge, giving rise to overpruning. Therefore, we sought to investigate possible interactions between a transgenic DISC1 model (tgDISC1) and juvenile immune activation (JIA) by the bacterial cell wall endotoxin lipopolysaccharide on the induction of schizophrenia-related behavioral and neurochemical disruptions in adult female and male rats. We examined possible behavioral aberrations along three major symptom dimensions of schizophrenia including psychosis, social and emotional disruptions, and cognitive impairments. We detected significant gene-environment interactions in the amphetamine-induced locomotion in female animals and in the amphetamine-induced anxiety in male animals. Surprisingly, gene-environment interactions improved social memory in both male and female animals. JIA alone disrupted spatial memory and recognition memory, but only in male animals. DISC1 overexpression alone induced an improvement in sensorimotor gating, but only in female animals. Our neurochemical analyses detected sex- and manipulation-dependent changes in the postmortem monoamine content of animals. Taken together, we here report sex-specific effects of environment and genotype as well as their interaction on behavioral phenotypes and neurochemical profiles relevant for schizophrenia.

Oligopeptidases activity in bipolar disorder: Ndel1 and angiotensin I converting enzyme.

BACKGROUND: Abnormal activity of two enzymes relevant to neurodevelopment, namely nuclear-distribution element-like 1 (Ndel1) and angiotensin I-converting enzyme (ACE), was reported in individuals with schizophrenia; to our knowledge, these oligopeptidases were never measured in bipolar disorder (BD). AIMS: Evaluate the enzyme activity of Ndel1 and ACE in euthymic individuals with BD type 1 which was compare to healthy control (HC) group. METHODS: Ndel1 and ACE activities were assessed in the serum of individuals with BD type 1 according to DSM-IV criteria (n = 70) and a HC group (n = 34). The possible differences between BD type 1 and HC groups were evaluated using Analysis of Covariance (ANCOVA), and the results were adjusted for age, gender and body mass index. RESULTS: We observed a positive correlation between Ndel1 activity and the total YMRS score in BD group (p = 0.030) and a positive correlation between ACE activity and Ham-D score (p = 0.047). ANCOVA analysis showed lower Ndel1 activity in BDs compared to HCs. Interestingly, we did not observe between-groups differences in ACE activity, despite the recognized correlation of ACE activity levels with cognitive functions, also described to be worsened in psychiatric patients. CONCLUSION: Oligopeptidases, especially Ndel1, which has been strongly correlated with neurodevelopment and brain formation, are potentially a good new target in the study of the neurobiology of BD. LIMITATIONS: The relatively small sample size did not permit to examine the cause-effect relationship of clinical dimensions of BD and the enzymatic activity.

Association study of Disrupted-In-Schizophrenia-1 gene variants and tardive dyskinesia.

Tardive dyskinesia (TD) is an involuntary movement disorder that occurs in ∼20% of patients after extended antipsychotic use. Its pathophysiology is unclear; however, familial patterns and gene association studies indicate an inherited component to risk. The disrupted in schizophrenia 1 (DISC1) gene was selected for analysis because it interacts with and regulates two important proteins involved in antipsychotic medication action: the dopamine D2 receptor and the cAMP phosphodiesterase type IVB (PDE4B). The D2 receptor is the obligate target of all existing antipsychotic medications, and PDE4B hydrolyzes cAMP, a core signaling molecule activated by agonist binding to the D2 receptor. Notably, PDE4B inhibitors such as rolipram have been shown to reduce TD-like behaviours in animal models. Nine single-nucleotide polymorphisms (SNPs) in the DISC1 gene were investigated in a sample of 193 chronic schizophrenia patients for association with the presence and severity of TD, with age and sex as additional variables. TD severity was measured using the Abnormal Involuntary Movement Scale (AIMS). Two DISC1 SNPs were associated with TD severity (uncorrected p < 0.05), but these findings did not survive correction for multiple testing. This preliminary investigation suggests that DISC1 gene variants do not affect risk for TD or severity.